The metabolic syndrome and type 2 diabetes have emerged as public health issues of considerable importance due to the magnitude of the problem and the associated high risk of atherosclerotic cardiovascular disease. New evidence supports a growing issue of increases in cardiovascular disease risk in people with Type 1 diabetes in part due to direct effects of glucose and evolving obesity in this population. The overall unifying theme is that components of the metabolic syndrome and diabetes leads to accelerated rates of atherosclerosis due to activation of key immune and inflammatory signals in the vascular wall and adipocytes. These factors further induce migration and activation of key cellular components into adipose tissue and the vascular wall. Aim#1--The hypothesis to be tested is that genetic or diet induced insulin resistance and diabetes will lead to accelerated inflammation, atherosclerosis, and macrophage infiltration into fat tissue. We will first characterize atherosclerosis progression in new mouse and porcine models of diabetes and the metabolic syndrome. The other key parameters that will be studied include analysis of visceral fat distribution (using DEXA) circulating adipokine production and evaluation of trafficking of macrophages into the visceral fat bed in collaboration with project 4. Aim#2--The goal of this aim is to specifically evaluate the role of 12/15 lipoxygenase (12/15-LO) and inflammatory pathways in visceral adipocytes and macrophages in vascular disease associated with the metabolic syndrome and diabetes. The hypothesis is that 12/15-LO activation participates in downstream inflammation in the vascular wall and visceral adipose tissue in large part by inducing activation and trafficking of macrophages. Aim#3?This is designed to test the hypothesis that key components of the innate immune system including toll like receptor 4 (TLR4) and the IL-12 family of cytokines participate in atherosclerosis in the insulin resistant and diabetic models. This overall project will utilize all cores and involve collaborations with Drs. Natarajan, McNamara, Ley, Hedrick, Gerrity, Susanna Keller, and Norbert Leitinger. The competitive renewal of our Project will utilize the latest cellular and molecular approaches and animal models to explore the mechanisms and new translational opportunities to reduce or prevent atherosclerotic cardiovascular disease associated with diabetes and the metabolic syndrome.